Max Planck Research Unit for Structural Molecular Biology at DESY

Proteins are folded into three-dimensional structures and modify their spatial arrangement dynamically in the course of biological reactions. The structural and functional relationships between proteins, multi-protein systems and the protein fibres in the cytoskeleton (microtubules) are examined in atomic detail at the Max Planck Research Unit for Structural Molecular Biology in Hamburg. X-ray crystal structure analysis is carried out using highly intensive synchrotron radiation sources at the Deutsches Elektronensynchrotron (DESY, German Electron Synchrotron). The scientists seek to explain, among other things, the role played by the tau protein in the emergence of Alzheimer’s disease. They also examine proteins from the tuberculosis bacterium to find starting points for the discovery of active agents to treat this disease. A large part of the research of Ada Yonath, who was awarded the Nobel Prize in chemistry in 2009, was carried out at this research unit. Here, she decoded the structure of ribosomes, the cell’s protein factories, and thus facilitated the search for innovative antibiotics.

The Max Planck Research Unit for Structural Molecular Biology at DESY was closed in July 2011.

Microtubules are protein fibres that are essential for determining the cells' shape, for cellular motion and cell division. In Alzheimer's disease, the microtubule-associated Tau protein, which is normally bound to the microtubule surface, forms characteristic aggregates in nerve cells. Transgenic cell and mouse models showed that the loss of synapses and neurons in Alzheimer's disease correlates with the aggregation of Tau. The concomitant impairment of learning and memory in mice can be reversed by suppression of Tau aggregation.
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The soil bacterium Arthrobacter nicotinovorans grows on nicotine. Degradation of L-nicotine and D-nicotine involves two genetically unrelated flavoenzymes, 6HLNO and 6HDNO. Their crystal structures may explain the stereospecificity of their enzymatic reactions. 6HLNO by its structure and mechanism is closely related to human monoamine oxidases (MAO), which play central roles in degradation of neurotransmitters. Structural analysis of 6HLNO reaction intermediates and the inhibition mechanism extends the basis for possible development of new leads for MAO.
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The "Cytoskeleton" group of the Max Planck Unit for Structural Molecular Biology in Hamburg focuses on the structure and dynamics of protein fibers in cells, in particular on microtubules and their associated proteins which are responsible for cell movement, cell division, or intracellular transport. One of these proteins, tau, forms pathological aggregates in nerve cells affected by Alzheimer's disease. Recent transgenic cell and mouse models of the tau pathology reveal that the pathological degeneration of synapses and neurons is closely related to aggregation, and that it is reversible.
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Tuberculosis represents a global health threat of escalating proportions, in particular due to the emergence of multi-drug resistant strains. Furthermore, little is known about the mechanisms applied by Mycobacterium tuberculosis to enter a dormant state, thus resisting to the immune defense system over long periods of time, and to reactivate itself. Identification of genes that are essential for virulence and survival of the pathogen, analysis of the three-dimensional structure of proteins encoded by these genes and studies of interactions with ligands may provide an important basis for possible directed development of new chemotherapeutic agents. Such a structural genomics approach has been followed by several groups and up to now have investigated about 200 target proteins.
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The "Max-Planck-Unit for Structural Molecular Biology" in Hamburg investigates the structure and function of biomolecules, with particular emphasis on the applications of synchrotron radiation for the elucidation of protein structures of biomedical interest. The "Cytoskeleton" group focuses on the structure, self-assembly, and dynamics of protein fibers in cells, in particular on microtubules and their associated proteins which are responsible for cell movement, cell division, cell differentiation, or intracellular transport. One of the microtubule associated proteins, tau protein, forms pathological aggregates in nerve cells affected by Alzheimer's disease. Recent findings reveal a linkage between tau's multiple functions and the cellular transport system which could prove essential for the aetiology of Alzheimer's disease.
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Protein function is determined by the three-dimensional structure and dynamical changes in the conformation during biological reactions. The structure-function relationships currently may be investigated in atomic detail even in the case of complex multi-protein systems. Such studies involve methods of X-ray crystal structure analysis that are based on the use of highly intense synchrotron radiation. The methods recently have been further developed, opening the way to structural genomics applications. The construction of free-electron lasers (FELs) at DESY provides the basis for entirely new types of applications in biological structural research. The VUV-FEL that recently has become operational at DESY may be used for Raman spectroscopic studies in the vacuum-UV on femtosecond time scales. The hard X-ray regime will be made accessible by the planned construction of an X-ray laser (X-FEL) at DESY. The X-FEL may be used for a number of applications including structural analysis of transient states on short time scales down to the femtosecond range, combined use of Mößbauer effect and diffraction for solving highly complex structures and simultaneous analysis of dynamical processes, and determination of the three-dimensional structures of non-crystalline matter and single (virus) particles.
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The "Cytoskeleton" group focuses on the structure, self-assembly, and dynamics of protein fibers in cells, in particular on microtubules and their associated proteins which are responsible for cell movement, cell division, cell differentiation, or intracellular transport. One of the microtubule associated proteins, the tau protein, forms typical aggregates in nerve cells affected by Alzheimer's disease. Recent findings reveal a linkage between tau's multiple functions and the cellular transport system which could prove essential for the aetiology of Alzheimer's disease.
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The interpretation of the genetic code and formation of functional proteins is performed by the ribosome. Structural studies of both ribosomal subunits revealed the specific interactions between the ribosome and its substrates. The results show, that ribosomes do not actively catalyse peptid bond formation, but rather position the substrate accurately, which facilitates and accelerates a thermodynamically favored reaction. Crucial for this mechanism is the internal symmetry within the catalytic core, which precisely reflects the symmetry of the substrates. Its universality makes the ribosome an attractive target for a large number of structurally diverse antibiotics. Almost all antibiotics targeting the large ribosomal subunit, bind in the same region: either directly in the peptidyl transferase center directly inhibiting peptide bond formation; or at the entrance of the ribosomal tunnel inhibiting elongation of the nascent protein. The most recent studies of such ribosome-antibiotic complexes revealed the inhibitory mechanism of two streptogramins. These compounds attack both sites simultaneously and in a synergistic manner, which induces a rather stable alteration of the peptidyl transferase center. The detailed knowledge of the specific interactions between different classes of antibiotics and the ribosome might facilitate and accelerate the development of urgently desired new drugs.
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